Pulmonary Hypertension in Connective Tissue Disease is Associated with the New York Heart Association Functional Class and Forced Vital Capacity, But Not with Interstitial Lung Disease

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Received：November 13, 2017, Revised：March 14, 2018, Accepted：March 28, 2018 Corresponding to：Chang-Hee Suh http://orcid.org/0000-0001-6156-393X

Department of Rheumatology, Ajou University School of Medicine, 164 WorldCup-ro, Yeongtong-gu, Suwon 16499, Korea.

E-mail：[email protected]

This is a Open Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Pulmonary Hypertension in Connective Tissue Disease is Associated with the New York Heart Association Functional Class and Forced Vital Capacity, But Not with Interstitial Lung Disease

Ju-Yang Jung¹, Chan Hee Lee², Hyoun-Ah Kim¹, Sang Tae Choi³, Joo-Hyun Lee⁴, Bo-Young Yoon⁴, Dae-Ryong Kang⁵, Chang-Hee Suh¹

1Department of Rheumatology, Ajou University School of Medicine, Suwon, ²Department of Rheumatology, National Health Insurance Service Ilsan Hospital, Goyang, ³Department of Rheumatology, Chung-Ang University College of Medicine, Seoul, ⁴Division of Rheumatology, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, ⁵Department of Medical Humanities and Social Medicine, Office of Biostatistics, Ajou University School of Medicine, Suwon, Korea

Objective. Pulmonary hypertension (PH) develops frequently in connective tissue diseases (CTD) and is an important prog- nostic factor. The aim of this study was to assess the prevalence of PH in patients with CTD by non-invasive echocardiography and analyze the potential biomarkers for helping to detect PH. Methods. All Korean patients with CTD who had dyspnea on exertion or interstitial lung disease (ILD) were screened for PH with echocardiography and clinical data were collected from four hospitals. Results. Among 196 patients with CTD, 108 (55.1%) had ILD and 21 had PH defined as ＞40 mmHg. Of the 21 patients with PH, 10, 4, and 3 patients had systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease, respectively. There was no difference in the incidence of PH according to the presence of ILD; 12 patients (11.1%) with ILD had PH and 9 patients (10.2%) without ILD had PH. The results of the pulmonary function test, total cholesterol, red cell volume distribution width, alkaline phosphatase, and the New York Heart Association (NYHA) functional class III or IV differed significantly according to the presence of PH. In multiple regression analysis, NYHA functional class III or IV (odd ratio [OR]=7.3, p=0.009) and forced vital capacity (OR=0.97, p=0.043) were independent predictive factors of PH. Conclusion.

PH is not associated with the presence of ILD in Korean patients with CTD. On the other hand, NYHA functional class III or IV and decreased forced vital capacity indicate the presence of PH in connective tissue disease. (J Rheum Dis 2018;25:179-187)

Key Words. Connective tissue disease, Pulmonary hypertension, Echocardiography, Interstitial lung disease, Risk factors

INTRODUCTION

Pulmonary hypertension (PH) is one of serious manifestations in connective tissue diseases (CTD) including systemic sclerosis (SSc), systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD) and rheumatoid arthritis (RA) [1]. PH is defined as an in- crease of resting mean pulmonary artery pressure (PAP)

＞25 mmHg with normal pulmonary capillary wedge pressure [2]. PH is characterized by medial hypertrophy,

intimal proliferative and fibrotic changes, and adventitial thickening with perivascular inflammatory infiltrates.

CTD-associated PH is known to have different features in accordance with the types of CTD and poorer outcome compared with idiopathic PH [3]. In SSc-associated PH, profibrotic cytokines such as transforming growth factor-β play a role in leading to obliterative vasculopathy, and its prognosis is reported more aggressive than in that of idiopathic PH [4,5].

In CTD, interstitial lung disease (ILD) and PH are the

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main manifestations involving the pulmonary system and the symptoms of these two diseases are similar. Chronic lung diseases including pulmonary fibrosis lead to the elevation of pulmonary artery pressure and right heart failure [6]. CTD-associated PH is known to originate, by different pathogenesis, from PH due to lung disease in which hypoxia induces vascular change [7]. In CTD-associated PH, autoimmune response mediates vascular hypertrophy and fibrosis in pulmonary artery and it ad- vances to a status without hypoxia. Consequently, CTD- associated PH has been reported to develop similarly in patients with ILD and those without, and acts as a major mortality factor independent of ILD [8,9].

The manifestations of PH are nonspecific as dyspnea with exertion, lower extremities edema, fatigue and palpitation. Usually, a patient may not feel anything until PAP highly increases [10]. There is no specific biomarker representing elevated PAP. Unless the physicians pay an attention to a possibility of pulmonary vasculature involvement, the diagnosis of PH might be delayed.

Recently, the new treatments for PH have been known ef- fective, so the timely detection and early intervention has been more important [5,11].

Echocardiography is a convenient and useful test to esti- mate a peak tricuspid regurgitation velocity (TRV) and pulmonary artery systolic pressure (PASP) in screening PH and to identify possible cardiac etiology [2,11-13]. In the patients with CTD having cardiac symptoms, echocardiography can provide essential information about the conditions that predispose to PH including pericardial ef- fusion and left sided valve changes [1,14]. Right heart catheterization (RHC) is recommended because it can confirm the diagnosis of PH as a more accurate and reliable examination, assess the severity and test the vaso- reactivity of the pulmonary circulation [1,2,14,15].

However, RHC is an invasive procedure that can result in some complications including hemorrhage and hema- toma, with a nearly 1% incidence [16]. It is difficult to take the risk of complication for the purpose of diagnosis, as many patients with CTD have a poor condition with complicated medications. A gap between the recommendation and the clinical practice of rheumatologist was reported to exist in the diagnosis of CTD-associated PH [17]. In Korean registry report, a number of patients received a diagnosis of PAH on the basis of only echocardiography because the frequency of RHC was low [18,19]. Moreover, pulmonary vascular resistance estimated by echocardiography was shown to closely corre-

late with that evaluated by RHC in patients with a forced vital capacity (FVC)/lung diffusion capacity for carbon monoxide (DLCO) ratio ＞1.6, which means that echocardiography can be a reliable marker in identifying PH noninvasively [20]. Moreover, PASP measured by using echocardiography was revealed to be associated with mortality regardless of the results of RHC [21].

Therefore, we aimed to investigate the possibility for PH by using echocardiography when a CTD patient has dyspnea on exertion or known ILD. In addition, we determined potential biomarkers of PH in patients with CTD.

MATERIALS AND METHODS

Study population and data collection

In Ajou University Hospital, National Health Insurance Service Ilsan Hospital, Chung-Ang University Hospital, Inje University Ilsan Paik Hospital, from February 2011 to October 2013, patients with CTD who had dyspnea on exertion were enrolled. The patients were diagnosed CTD by the established classification criteria of each disease such as SSc by Classification criteria for SSc: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative at 2013, SLE by Systemic Lupus International Collaborating Clinics Classification Criteria for SLE at 2012 and RA by 2010 RA classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative [22-24]. Moreover, CTD patients who had ILD confirmed with chest high-resolution com- puter tomography (HRCT) were included irrespective of symptoms. All of them underwent transthoracic echocardiography, and most patients took pulmonary function test (PFT) with DLCO except for a few patients who could not exhale enough for the measurement. The medical re- cords and laboratory results of aspartate aminotransferase, alanine aminotransferase, total cholesterol, red cell volume distribution width (RDW), alkaline phosphatase (ALP) and uric acid were collected. Symptom of dyspnea was described according to New York Heart Association (NYHA) functional classification.

Measurements

Echocardiography was performed at each hospital by skillful examiners. PASP was calculated from maximal tricuspid regurgitation velocity (TRVmax) using the sim- plified Bernoulli formula as follows: PASP=4×(TRVmax) 2+right atrial pressure (calculated with 5 mmHg as nor-

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Table 1. The clinical characteristics of patients (n=196)

Clinical factor Value

Age (yr) 54.8±14.7

Gender, female:male 150:46

Disease duration (mo) 43.2±52.8 Interstitial lung disease 108 (55.1) Disease

Systemic sclerosis 62 (31.6)

Rheumatoid arthritis 54 (27.6) Systemic lupus erythematosus 43 (21.9)

Myositis 16 (8.2)

Mixed connective tissue disease 7 (3.6)

Others 14 (7.1)

NYHA functional class

I 75 (38.3)

II 105 (53.6)

III 15 (7.7)

IV 1 (0.5)

Mortality 4 (2.0)

Echocardiographic finding

TRV (m/s) 2.49±0.43

PASP (mmHg) 30.5±9.8

PFT finding (%)

DLCO 67.4±22.4

FVC 82.9±21.7

FEV1 87.0±23.2

FVC/DLCO 1.32±0.34

Laboratory finding

RDW (%) 14.4±2.1

AST (U/L) 33.8±51.4

ALT (U/L) 25.8±42.2

Total cholesterol (mg/dL) 177.1±44.4

ALP (U/L) 69.7±31.7

Uric acid (mg/dL) 4.5±1.4

Medication

Corticosteroid 135 (68.9)

Hydroxychloroquine 77 (39.3)

Azathioprine 37 (18.9)

Methotrexate 32 (16.3)

Penicillamine 13 (6.6)

Bucillamine 27 (13.8)

Sulfasalazine 14 (7.1)

Tacrolimus 26 (13.3)

Cyclophosphamide 20 (10.2)

Calcium channel blocker 34 (17.3) Endothelial receptor antagonist 9 (4.6) Prostacyclin analogues 6 (3.1)

Values are presented as mean±standard deviation, number only or number (%).

NYHA: New York Heart Association, TRV: tricuspid regurgitation velocity, PASP: pulmonary artery systolic pressure, PFT:

pulmonary function test, DLCO: lung diffusion capacity for carbon monoxide, FVC: forced vital capacity, FEV1: forced expired volume in one second, RDW: red cell volume distribution width, AST: aspartate aminotransferase, ALT:

alanine aminotransferase, ALP: alkaline phosphatase.

mal) [25]. This study was approved by the institutional review board of each hospital and informed consent was obtained from each patient (IRB no. AJIRB-MED-MDB- 10-330).

Statistical analysis

Group comparisons divided by the presence of PH and ILD were conducted by using independent t-tests for con- tinuous data and the Mann-Whitney U-test for non- parametric data. Logistic regression analysis was performed to determine the variables associated with an increased risk for PH. Univariate regression analysis was conducted with age, sex, the presence of ILD, DLCO, FVC, forced expired volume in one second (FEV1), aspartate aminotransferase, alanine aminotransferase, total cholesterol, RDW, ALP, uric acid and NYHA functional class (FC) III or IV as independent variables. Six variables had statistical significance, and those were adjusted in multivariate analysis. In Hosmer-Lemeshow good- ness-of-fit statistic, their p-value was 0.872, and their var- iance inflation factors showed they had no multicoll- inearity. A two-tailed p-value ＜0.05 was used to indicate statistically significant differences. All computations were performed using the SPSS statistics version 22.0 (IBM Co., Armonk, NY, USA) and MedCalc version 14.10.2 (MedCalc software, Ostend, Belgium).

RESULTS

Clinical characteristics of patients with CTD One-hundred ninety-six patients were recruited (female, 150 patients), with a mean age was 54.8±14.7 years and mean disease durations of 43.2±52.8 months (Table 1).

The common underlying diseases were SSc in 62 patients, RA in 54 patients, and SLE in 43 patients. The mean TRV was 2.49±0.43 m/sec and estimated PASP was 30.5±9.8 mmHg. One-hundred eight patients had ILD that was confirmed by HRCT or lung biopsy. The FVC, FEV1 and DLCO were 82.9±21.7%, 87.0±23.2% and 67.4±22.4%, respectively. Most patients (180/196, 91.8%) felt mild symptom of dyspnea such as NYHA FC I or II, 15 patients were NYHA FC III and 1 patient was NYHA FC IV.

One-hundred thirty-seven patients were taking gluco- corticoids, 77 were taking hydroxychloroquine and 37 were taking azathioprine. As the treatment for PH, 9 patients were taking endothelial receptor antagonists and 6 patients were taking prostacyclin analogue. During 32 months, the period of this study conducted, four patients

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Table 2. The comparison of the patients with ILD and those without

Clinical factor ILD (n=108) No ILD (n=88) p-value

Age (yr) 55.7±14.3 53.8±15.1 0.302

Gender, female:male 81:26 69:20 0.706

NYHA functional class III/IV, n (%) 9 (8.3) 7 (8.0) 0.848

Echocardiographic finding

TRV (m/s) 2.5±0.4 2.5±0.4 0.808

PASP (mmHg) 30.8±9.6 30.1±10.1 0.455

PFT finding (%)

DLCO 60.7±21.2 (92*) 75.5±21.3 (79*) ＜0.001

FVC 73.9±19.6 (96*) 93.5±19.2 (82*) ＜0.001

FEV1 79.5±5.46 (96*) 95.7±22.3 (82*) ＜0.001

FVC/DLCO 1.3±0.4 (91*) 1.3±0.3 (78*) 0.346

Laboratory finding

RDW (%) 14.2±1.8 (107*) 14.6±2.4 (88*) 0.215

AST (U/L) 36.6±65.2 (107*) 30.5±26.4 (88*) 0.913

ALT (U/L) 28.5±55.5 (107*) 22.6±14.9 (88*) 0.160

Total cholesterol (mg/dL) 175.3±38.7 (101*) 179.1±50.1 (88*) 0.552

ALP (U/L) 108.5±87.9 (102*) 105.5±93.8 (88*) 0.481

Uric acid (mg/dL) 4.5±1.5 (97*) 4.6±1.3 (85*) 0.895

ILD: interstitial lung disease, NYHA: New York Heart Association, TRV: tricuspid regurgitation velocity, PASP: pulmonary artery systolic pressure, PFT: pulmonary function test, DLCO: lung diffusion capacity for carbon monoxide, FVC: forced vital capacity, FEV1: forced expired volume in one second, RDW: red cell volume distribution width, AST: aspartate aminotransferase, ALT:

alanine aminotransferase, ALP: alkaline phosphatase. *The number of patients tested.

Table 3. The prevalence of increased PASP according to ILD pattern in CTD

ILD pattern Total (n=108) PH (n=12)

Usual interstitial pneumonia 42 5 (11.9)

Nonspecific interstitial pneumonia 36 5 (13.9)

Undifferentiated interstitial lung disease 21 1 (4.8)

Bronchiolitis obliterans organizing pneumonia 9 1 (11.1)

Values are presented as number only or number (%).

PASP: pulmonary artery systolic pressure, ILD: interstitial lung disease, CTD: connective tissue disease, PH: pulmonary hypertension, pulmonary artery systolic pressure ＞40 mmHg.

died and two of them had PH. The causes of deaths were respiratory failure due to aggravation of ILD (two patients), sepsis (one patient) and cardiogenic shock due to progressed aplastic anemia (one patient).

Comparison of ILD and non-ILD patients

Among 196 patients with CTD, 108 patients (55.1%) had ILD which confirmed by HRCT or lung biopsy (Table 2). There was no difference in the incidence of patients with PH according to the presence of ILD; in the patients with ILD, 12 patients had PH (12/108, 11.1%), and in those without ILD, 9 patients had PH (9/88, 10.2%).

Between the two groups which divided according to the

presence of ILD, the patients’ age, sex, TRV and PASP were not different; however, FVC, FEV1 and DLCO showed significant differences (Table 2). In addition, other clinical variables including RDW, liver function, total cholesterol, uric acid and NYHA FC were similar. Usual interstitial pneumonia was most common with 42 patients, followed by nonspecific interstitial pneumonia was following with 36 patients (Table 3).

Clinical characteristics of patients with PH With the defining PH as estimated PASP ＞40 mmHg measured by echocardiography, 21 patients were determined to have PH with mean PASP 52.2±10.5 mmHg

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Table 4. The clinical characteristics in the patients with PAH

Variable PAH (n=21) No PAH (n=175) p-value

Age (yr) 56.6±19.8 54.6±14.0 0.567

Gender, female:male 19:3 131:43 0.295

Disease duration (mo) 37±43.7 42.9±51.6 0.908

Presence of ILD 12 (54.5) 96 (55.2) 0.843

Disease

SSc 10 (16.1) 52 (83.9)

RA 2 (3.7) 52 (96.3)

SLE 4 (9.3) 39 (90.7)

MCTD 3 (42.9) 4 (57.1)

NYHA functional class III/IV 8 (36.4) 8 (4.6) ＜0.001

Echocardiography data

TRV (m/s) 3.4±0.3 2.38±0.2 ＜0.001

PASP (mmHg) 52.2±10.5 27.8±5.6 ＜0.001

PFT data (%)

DLCO 60.6±24.1 (13*) 68.1±22.1 (158*) 0.246

FVC 63.2±28.3 (18*) 85.1±19.8 (160*) ＜0.001

FEV1 68.7±34.4 (18*) 89.1±20.9 (160*) 0.024

FVC/DLCO 1.3±0.3 (14*) 1.3±0.4 (155*) 0.948

Laboratory data

RDW (%) 15.1±3.1 14.2±1.8 0.041

AST (U/L) 32.0±18.7 34.0±54.0 0.736

ALT (U/L) 18.9±12.8 26.6±44.4 0.432

Total cholesterol (mg/dL) 147.7±40.1 (17*) 179.9±43.7 (172*) 0.004

ALP (U/L) 87.5±35.5 (20*) 67.9±30.7 (171*) 0.027

Uric acid (mg/dL) 5.0±1.9 (19*) 4.4±1.2 (163*) 0.105

PAH: pulmonary arterial hypertension, ILD: interstitial lung disease, SSc: systemic sclerosis, RA: rheumatoid arthritis, SLE: systemic lupus erythematosus, MCTD: mixed connective tissue disease, NYHA: New York Heart Association, TRV: tricuspid regurgitation velocity, PASP: pulmonary artery systolic pressure, PFT: pulmonary function test, DLCO: lung diffusion capacity for carbon monoxide, FVC: forced vital capacity, FEV1: forced expired volume in one second, RDW: red cell volume distribution width, AST:

aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase. Pulmonary hypertension: pulmonary artery systolic pressure ＞40 mmHg. *The number of patients tested.

(Table 4). Among the patients with PH, 10 had SSc, 4 had SLE and 3 had MCTD. There was no difference in the age, sex, disease duration and presence of ILD between patients with PH and those without. More than one-third of patients with PH had functional limitation due to dyspnea (NYHA FC III or IV), which was significantly more severe than those without PH (8 [36.4%] vs. 8 [4.6%], p＜

0.001). While the values of DLCO were a little different between these patients, FVC and FEV1 were significantly lower in patients with PH (63.2±28.3% vs. 85.1±19.8%, p＜0.001; 68.7±34.4% vs. 89.1±20.9%, p=0.024, respectively). From a previous study, a FVC/DLCO ratio of

＞1.6 was reported to be a diagnostic marker for PH in SSc [24], but it was not related with PH in this study. RDW means a variability in the size of circulating red blood cells and RDW was higher in the patients with PH than in

those without (15.1±3.1% vs. 14.2±1.8%, p=0.041).

Patients with PH had significantly lower total cholesterol than those without (147.7±40.1 mg/dL vs. 179.9±43.7 mg/dL, p=0.004). The level of ALP in patients with PH was significantly more elevated (87.5±35.5 U/L vs.

67.9±30.7 U/L, p=0.027).

Predictors of PH development in patients with CTD

On univariate regression analysis with the variables which were different between CTD patients with PH and those not, NYHA FC III/IV, FVC, FEV1, RDW, total cholesterol and ALP were correlated with the presence of PH in CTD (Table 5). On multiple regression analysis, NYHA FC III or IV (odds ratio [OR]=7.3, p=0.009) and FVC (OR=0.97, p=0.043) were found to be related with PH.

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Table 5. The logistic regression analysis for PAH in connective tissue disease

Variable Univariate Multivariate

OR (95% CI) p-value OR (95% CI) p-value

NYHA functional class 9.22 (2.98, 28.5) ＜0.001 7.3 (1.7, 32.12) 0.009

FVC 0.95 (0.93, 0.98) ＜0.001 0.97 (0.94, 1.0) 0.043

FEV1 0.96 (0.94, 0.98) 0.001 1.01 (0.94, 1.07) 0.846

RDW 1.23 (1.03, 1.46) 0.019 1.05 (0.58, 2.0) 0.780

Total cholesterol 0.98 (0.96, 0.99) 0.004 0.99 (0.97, 1.00) 0.125

ALP 1.01 (1.00, 1.03) 0.016 1.01 (1.00, 1.03) 0.062

PAH: pulmonary arterial hypertension, OR: odds ratio, CI: confidence interval, NYHA: New York Heart Association, FVC: forced vital capacity, FEV1: forced expired volume in one second, RDW: red cell volume distribution width, ALP: alkaline phosphatase.

Figure 1. Receiver operating characteristic to predict pulmo- nary hypertension by echocardiography in connective tissue disease. The area under curve (AUC) of receiver operating characteristic by final model with New York Heart Association functional class III or IV and forced vital capacity was 0.767.

Area under curve (AUC) of receiver operating characteristic determined by NYHA FC III or IV and FVC was 0.767 (Figure 1).

DISCUSSION

This is an observational study that investigated the clinical features of PH among patients with CTD in Korea and the purpose was to determine the characteristics of CTD patients with PH.

We defined PH as PASP ＞40 mmHg on echocardiography. PH was categorized as moderate if PASP is

＞55 mmHg and mild if PASP is 40 to 54 mmHg [26]. In addition, echocardiographic TRV ≥3 m/sec and/or PASP

≥40 mmHg were used as thresholds indicating possible PH [27]. While some studies defined possible PH if a PASP was ＞35 mmHg, PASP ＞40 mmHg as definition of PH

was more reliable in a study conducted without RHC [28].

PH is combined 7%∼27% in patients with SSc, which is characterized by the presence of vasculopathy and fibrosis of multiple organs due to autoimmune imbalance [29]. With lung fibrosis, PH is a typical disorder with lung involvement and a poor prognostic factor with higher mortality in patients with SSc. SSc-associated PH seems to be more aggressive and shows poorer outcomes than idiopathic PH or other CTD-associated PH [3]. In patients with SLE, the prevalence of PH was reported with variety from 0.5% to 14% [30], although PH is not common compared with other manifestations. Although SLE was recently reported the most common underline disease in Chinese patients with CTD associated PH [31], our study showed similar prevalence (9.3%) to western data. PH is known to be rare in patients with RA; however, the mean pulmonary artery pressures measured by echocardiography were reported to be elevated and the prevalence of PH was higher in the patients with RA than in healthy controls (21% vs. 4%, respectively) [32]. In this study, 2 of 52 patients with RA had PH, and the development of PH in patients with RA was lower than in those with SSc, SLE or MCTD. MCTD is an autoantibody (anti- ribonucleoproteins (RNP) antibody)-mediated disease with Raynaud’s phenomenon, arthritis, sclerotic change of skin, serositis, myositis and pulmonary fibrosis.

Although MCTD is a rare disease and is almost impossible to study because the small number of cases, the prevalence of PAH had been estimated as 50%∼60%

[10]. In this study, seven patients with MCTD were enrolled and four of them had PH. We suggest performing echocardiography frequently in patients with MCTD.

PFT is a basic diagnostic tool that determines the type of pathophysiology of lung disease, e.g. the presence or ab- sence of an obstructive or a restrictive pattern, and PFT

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with DLCO has been used in diagnosis of and monitoring for ILD and PH [33]. On the basis of the change of the al- veolar capillary membrane and ventilation/perfusion ratio, DLCO was reported to be decreased in CTD-associated PH, especially in SSc [34]. DLCO was reported as a most reliable marker for progression of PAH in SSc, and FVC/DLCO ＞1.6 was suggested as a useful marker in the diagnosis of PH in patients with SSc [26], but it was not different according to the presence of PH among our patients with CTD and SSc. DLCO was not different, but FVC and FEV1 were significantly different in the patients with PH compared to those not. In addition, low FVC was associated independently with the presence of PH in patients with CTD, while FEV1 was not.

NYHA FC was originally developed for evaluation of cardiac disease and it was adopted to access the limitation of physical activity of PH by the World Health Organization.

Despite the sizeable interrater variation in the NYHA FC, studies showed that patients with FC III or IV had a worse prognosis than those with FC I or II [35,36]. Further- more, NYHA FC is a key predictor of diagnosis for PH and regulatory approval of PH therapy [37]. In the present study, more than one-third of patients with PH had NYHA FC III or IV, which was significantly more frequent than those without PH. In addition, NYHA FC III or IV was independently associated with PH.

RDW is a quantitative measure of the variability in size of the circulating erythrocytes and it becomes elevated when ineffective red cells are produced. The tentative mechanisms between RDW and such heart problems are anemia from poor circulation, inflammatory stress, nutri- tional deficiencies and insufficient production of eryth- ropoietin [38]. RDW was increased in chronic throm- boembolic pulmonary hypertension and was identified to reflect poor prognosis in patients with PH [39]. In here, RDW was elevated in patients with PH than those not.

ALP is synthesized in liver and bone, and its elevation is predominantly due to its increased synthesis in hep- atocyte and consequent release into circulation in extra- hepatic biliary obstruction. ALP and γ–glutamyl transferase was increased in patients with PH, and it may be caused by cardiac congestion and elevated right atrial pressure [40]. In CTD associated PH, ALP was reported as a predictor for mortality [32]. Significantly elevated ALP was noted in patients with PH, but not associated with PH independently.

Combination of NYHA FC III or IV and FVC were re- garded as a reliable predictive marker for PH in CTD

(AUC=0.767). Although NYHA functional classification is a marker including subjective part in defining dyspnea, the symptom severities of patients with NYHA III or IV will be different those with NYHA I or II. During fol- low-up, aggravated dyspnea and reduction of FVC in patients with CTD might suggest development of PAH regardless of DLCO or ILD.

In this study, there was no difference between the patients with ILD and those without in terms of the development of PH. A study with large number of the patients with CTD associated PH (n=641) showed that an accom- panying mild ILD on HRCT was more frequent in patients with CTD than in patients with idiopathic PH [3]; however, the correlation of ILD and PH in patients with CTD was not analyzed. The relation between ILD and PH in patients with CTD has been rarely studied, and our data show that PH in CTD may occur independent of ILD. The patients with CTD should be checked for the presence of PH even if they do not have ILD.

This study has several limitations. PH was not diagnosed in current practical recommendation, most of patients were diagnosed PH by echocardiography without confirmation with RHC. The reports demonstrated the estimated pulmonary pressure by echocardiography was correlated with that measured by RHC and associated with mortality [13,19,20]. The small sample size of each CTD made it impossible to identify more characteristics according to each disease. We hope to conduct a pro- spective study with RHC in Korean patients with CTD in near future.

CONCLUSION

Among total 196 patients with CTD, 21 patients had a diagnosis of CTD-associated PH, which was defined as a PASP ＞40 mmHg measured by echocardiography. There was no difference in the prevalence of PH in CTD patients with ILD and those without. NYHA FC III or IV and decreased forced vital capacity suggested the presence of PH in connective tissue disease (76.7%).

ACKNOWLEDGMENTS

We gratefully acknowledge the contribution of Handok for research funding and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant no.

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HI14C1731 and HI16C0992).

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

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